Inflammatory bowel disease (IBD) is a disorder of unknown etiology characterized typically by diarrhea, cramping, abdominal pains, weight loss and rectal bleeding, tiredness, anemia, fistulae, perforations, obstruction of the bowel and frequent need for surgical intervention. According to the US Center for Disease Control and Prevention, about 1.4 million people in USA suffer from IBD, making it one of the most prevalent gastrointestinal diseases in the United States. The overall healthcare cost of IBD in USA is estimated to be more than US$1.7 billion per year.
A number of disorders fall within the class of IBD, including Crohn's disease, ulcerative colitis, indeterminate colitis, microscopic colitis and collagenous colitis. The most common forms of IBD are Crohn's disease and ulcerative colitis. Ulcerative colitis affects the large intestine (colon) and rectum and involves the inner lining (e.g., the mucosal and sub-mucosal layer) of the intestinal wall. Crohn's disease may affect any section of the gastrointestinal tract (e.g., mouth, esophagus, stomach, small intestine, large intestine, rectum, anus, etc.) and may involve all layers of the intestinal wall. The clinical symptoms of IBD include rectal and/or intestinal bleeding, abdominal pain and cramping, diarrhea, and weight loss. In addition, IBD is a risk factor for colon cancer, and this risk for colon cancer increases significantly after eight to ten years of IBD.
IBD has no cure. Current therapies for IBD are directed at reducing the inflammatory process and at reducing the detrimental effects of the inflammatory process associated with the disease, and include administration of anti-inflammatory drugs (e.g., mesalamine, sulfasalazine, infliximab, adalimumab, prednisone, budesonide) and of immunosuppressive drugs (e.g., 6-mercaptopurine, azathioprine, cyclosporine). Such therapies are often associated with adverse side effects, such as nausea, vomiting, anorexia, dyspepsia, malaise, headaches, abdominal pain, fever, rash, pancreatitis, bone marrow suppression, formation of antibodies, infusion reactions, and increased opportunistic infections.
It is clear from the foregoing that treatments for IBD are required.
Certain patent applications speculate that antibodies that neutralize granulocyte-macrophage colony stimulating factor (GM-CSF) signaling may be a potential treatment for a variety of autoimmune conditions, including arthritis, multiple sclerosis, lung inflammation, atheroscelerosis and IBD. Despite this speculation, research conducted in the field of treating IBD suggests that GM-CSF itself may be a therapeutic agent for this disorder. For example, Sainathan et al., (Inflamm Bowel Dis. 14: 88-99, 2008) showed that GM-CSF significantly improved clinical parameters in a model of colitis. Studies in humans have also shown that Sargramostim (GM-CSF) provides a benefit in some patients suffering from Crohn's disease (e.g., Korzenik et al., N Engl J Med. 352: 2193-201, 2005; Takazoe et al., J Gastroenterol. 44: 535-43, 2009; Valentine et al., Gut. 58:1354-62, 2009; and Kelsen et al., Inflamm Bowel Dis. 16:1203-8, 2010). For example, Korzenik et al., showed a significant increase in the number of patients receiving treatment with Sargramostim who achieved a reduction of Crohn's Disease Activity Index (CDAI) of 100 points or entered remission compared to placebo. These results are consistent with the findings of Goldstein et al., (Gastroenterology 141: 208-216, 2011) who showed that decreased levels and activity of GM-CSFR is associated with IBD in humans. These findings indicate that IBD is different to several other autoimmune disorders, in which administering GM-CSF actually exacerbates the symptoms of the disorder, e.g., arthritis, multiple sclerosis, lung inflammation or atheroscelerosis.